Childhood and Young Adult Cancer in

The Jerusalem Perinatal Study(JPS)

Ora Paltiel

School of Public Health and Dept of Hematology, Hadassah-Hebrew

University, Jerusalem Israel

JPS

• Research cohort established in 1964-76

• All births to residents of West Jerusalem (92,408 children; 42,956 mothers; 39,620

fathers)

• Active surveillance of infant mortality, birth defects and pregnancy complications

Harlap et al Paed Perinatal Epidemiology 2007; 21:256-73.

J e r u s a l e m P e r i n a t a l S t u d y

Age 17

Follow up cancer and mortality

Mass immigration to Israel

*Preconception

Pregnancycomplications

and outcomes

Life events after delivery

cancer

mortality

time

To what extent do events during early

human development or peripartum affect

cancer incidence and mortality over a

lifetime in the Israeli population?

JPS cancer types age <15

Leukemias; 41

Lymphomas; 39

Nervous system; 37

Neuroblastoma; 10

Retinoblastoma; 7

Nephroblastoma; 5

Carci-noma;

4

Rhab-domyosarco ma, 2

bone; 18

other; 9

Birth Weight and Cancer

• Low birth weight traditionally considered risk factor for future health outcomes

• Recent concern regarding effects of high birth weight

• Relation between high birth weight and cancer in children and adults

• Most consistent relationship: high birth weight and acute leukemia

Proposed mechanisms:• Growth factors – eg IGF-1 related both to birthweight and

carcinogenesis

• Hormone levels eg estriol – related to fetal growth and breast cancer

• Genomic imprinting – syndromes related to both macrosomia and tumors

• Genetic susceptibility- genes related to birth weight and cell proliferation

• N - Larger population of preneoplastic clones

• Exposures eg pelvic radiation in mothers with large babies

In 2000: 88,829 (97.1%) offspring from the JPS were traced and linked to the Israel Cancer Registry

Methods:

Objective:

To evaluate the association between birth weight

and leukemias in the JPS

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004

High Birth Weight and Cancer

Distribution of birth weights JPSall newborns vs children with cancer

birth weight (kg)

Fre

qu

en

cy

20000

15000

10000

5000

0

Std. Dev = .54

Mean = 3.25

N = 86647.00

birth weight (kg)F

req

ue

ncy

80

60

40

20

0

Std. Dev = .50

Mean = 3.32

N = 499.00

1.00

2.21

3.09

3.96

0

1

2

3

4

5

<3000 3000-3499 3500-3999 ≥4000birth weight (gram)

RR

RR for all leukemia n=65 by birth weight

RR for ALL n=41 RR for AML n=21

P for linear trend = 0.002

1

4.193.76

4.63

0

1

2

3

4

5

<3000 3000-3499 3500-3999 ≥4000birth weight (gram)

RR *

**

*P <0.05

1 0.72

2.593.46

0

1

2

3

4

5

<3000 3000-3499 3500-3999 ≥4000birth weight (gram)

RR

*

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2004

Birth weight and its relation to other cancers

• All sites (860) …………………. 2.05 (1.36-3.10) • Lymphoma (170) ………………1.50 (0.90-2.50)• Sarcoma (47) …………………..2.08 (0.87-4.90)• Breast cancer (96) ……………. 0.45 (0.14-1.43) • Melanoma (65) …………………2.32 (1.13-4.78) • Thyroid (96) …………………….0.52 (0.17-1.67)• Testicular (50) ………………….2.29 (1.02-2.75)

*Adjusted for maternal age at birth, gender (where relevant), socioeconomic status, ethnic origin of mother and family history

RR* for birthweight >4000gm (compared to 2500-3999 gm)

Cancer site (N)

Paltiel O, Deutsch L, in prep

Having high BW sibling and leukemia

• For any sibling weighing >3500 gm• All leukemias: HR 1.94(1.2-3.1)• For ALL: HR 1.48 (0.8-2.8)• For AML: HR 3.1(1.4-7.1)

Relative risk of leukemia of mothers by offspring birthweight

0

0.5

1

1.5

2

2.5

3

3.5

4

>1500 1500-4499

<4500

Rel

ativ

e R

isk

Birthweight (gr)

*

Ref.

Paltiel O et al Leukemia Res. 2008

Cancer in children with congenital malformations

Preliminary results from the JPS

Paltiel, O, Yanetz R in prep

Carcinogenesis and teratogenesis may be related

The cause of most birth defects is unknown

Furthermore, risk factors for cancer in children and young adults are largely undiscovered

Genes and developmental processes involved in fetal development may also be important in neoplasia

Background-evidence

• Down syndrome: increased risk of leukemia

• Other genetic diseases – Beckwith Wiedemann, Goldenhar, Sturge-Weber etc increased risk of specific neoplasms

• Previous studies have been case reports, case series and occasionally case control studies

Demographic characteristics of children born with and without malformations

With Without

Male 64% 51%

Birthweight <2500 gm 10% 7%

Mother smoker 28% 23%

Mother’s age at birth >35 13% 12%

Father’s age at birth >35 27% 27%

Cancer in children with and without malformations

Relative Risk (95% CI)1.35) 1.06-1.71 (p=0.01

0

0.5

1

1.5

2

Severity of malformation

Rel

ativ

e R

isk

mild/moderate severe

)0.88-1.72(

)1.18-2.27(

P=0.03

Severity of malformations and risk of cancer(compared to those without malformations)

0

1

2

3

4

solid tumors breast sarcoma testis

Rel

ativ

e R

isk

mild moderate severe

)0.99-2.11(

)0.38-6.4(

)0.32-5.28(

)2.96-6.74(

)0.29-5.02(

)1.21-9.39(

)0.98-5.36(

)0.38-6.4(

Are congenital anomalies related to cancer in siblings or parents

• No association in siblings• Association between cleft lip/palate with

genitourinary cancer in parents (esp. mothers)

The Risk of Cancer following Hospitalization for Infection in Infancy

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

Objective: to evaluate the relation between hospital admission

in the 1st year of life due to infectious disease and the risk of

developing malignancy in childhood and early adulthood.

Controversial relation between infections in infancy and subsequent cancer risk in

children and young adults

Childhood ALL, Hodgkin’s lymphoma

Protective effect of early infectious exposures

Non–Hodgkin’s lymphoma

1. Possibly induced by infectious stimulation

2. Immune defects and immunosuppression known risk factors.

Methods:

27,401 offspring: Complete information on hospital admissions in the 1st year of life

Exposed - at least one hospital admission due to infectious disease in the 1st year of life.

Nonexposed - no hospitalization for infection in the 1st year of life

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

2,016 (8%) were admitted at least once for infectious causes in the 1st year of life.

Hospitalization for infection related to:

Lower birth weight

Higher birth order

Lower socioeconomic status

Less educated mothers

Results:

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

HospitalizedNot

Hospitalized

n n RR P

Any malignancy 21 262 0.88 0.59

Leukemia 1 25 0.44 0.45

Non–Hodgkin’s lymphoma

6 19 3.46 0.019

We found a 3-fold increased risk of non–Hodgkin’s lymphoma after 1st year hospitalizations due to infectious diseases.

Paltiel O et al. Cancer Epidemiol Biomarkers Prev 2006.

Children with a minor immunologic defects

Speculated mechanism:

Infection↑ Non-Hodgkin Lymphoma

High mortality in the past

Higher survival at present

Could this be one of the causes of the increase in NHL incidence observed worldwide?

Age-adjusted Incidence of non-Hodgkin Lymphoma (NHL) US

Familial cancer in the JPS

• Most cancers are sporadic

• Rare opportunity (outside Scandinavian family cancer registries) to study familial cancers in a population-based study

• Heritable germline mutations are common in the Israeli population

– BRCA 1 breast, ovarian – BRCA 2 breast, prostate – APC Colon

Maternal region of origin-JPS

33%

29%

23%

15%

Israel Asia Africa West

35%

31%

20%

14%

47% 25%

18%

10%

Offspring with cancer (N=1093)

Mother-Offspring Pairs (N=176)

All Offspring (N=91,459)

Distribution (%) of cancer sites for mothers with and without affected

offspring

22.6

42

9

19

47

9

0%

20%

40%

60%

80%

100%

Mothers withoutaffected offspring

Mothers with affectedoffspring

NHL

Ovary

Cervix

Thyroid

Uterus

Melanoma

Colorectal

Breast

Other

Paltiel et al Fam. Cancer 2007;6:121-129

Distribution of cancer sites for offspring with and without affected mothers

35.8

12.2

8.9

8.7

8.4

7.5

26.6

4.8

10.5

12.4

13.3

10.5

0%

20%

40%

60%

80%

100%

Offspring without affectedmothers

Offspring with affectedmothers

Medulloblastoma

Sarcoma

MelanomaTestis

NHL

Thyroid

Leukemia

BreastHodgkin Disease

Other

Paltiel et al Fam. Cancer 2007;6:121-129

Cancers among sib-ships

N=16 families

• 25% of mothers also had malignancy• In 50% of families sites were concordant :

Lymphoma (N=3)

Breast (N=2)

Ovary (N=1)

Testis (N=1)

Melanoma (N=1)

Cancers among sib-ships

N=16 families

• 25% of mothers also had malignancy• In 50% of families sites were concordant :

Lymphoma (N=3)

Breast (N=2)

Ovary (N=1)

Testis (N=1)

Melanoma (N=1)

Family #1

3 siblings diagnosed within 4 years (1970-1974)

Family #2

2 siblings diagnosed within 3 years (1965-1968)

DISTRIBUTION OF THE TIME INTERVAL BETWEEN DIAGNOSIS OF MOTHER-CHILD PAIRS: OBSERVED & EXPECTED BY CHANCE

0

10

20

30

40

1.50 4.50 7.50 10.5 13.5 16.5 19.5 22.5 25.5 28.5 31.5years

freq

uen

cy

observed expected

Absolute interval (yrs) between diagnosis of mother and offspring

Paltiel et al Fam. Cancer 2007;6:121-129

Familial Cancer JPS: Next steps

• Updated linkage with cancer registry• Detailed analysis of updated offspring-mother,

offspring-father and sibling pairs• Mother-Father pairs: clues to environmental

etiologies• Eventually…..detailed epidemiologic study

including genetic, epigenetic and extensive exposure analysis

Preconception

Pregnancycomplications

and outcomes

Life events after delivery

cancer

time

Summary:

Exposures during the pre,peri- and postnatal period, have an impact on parents’ and offspring’s cancer risk.

• Unique population• Unique opportunities• Unique findings, requiring

confirmation in other populations• Potential for collaborations

Acknowledgments• JPS staff 1964-2007: Investigators, nurses and

field workers and statisticians• Current team:

Investigators: R. Calderon-Margalit, Y. Friedlander, O. Manor,V. Meiner, O.Paltiel

• PhD candidates: M Avgil, H Hochner, E. Tiram, Y Wolff

• Statisticians and Programmers: L. Deutsch, N. Sharon, R. Yanetz

• Research collaborators for Israel: U. Elchalal, D. Hochner, R. Pollock A. Samuelov, D. Varon, E . Hayam

• Columbia University, New York K.R. Kleinhaus, M.C.Perrin, A.I.Neugut, M.B.Terry, S.Harlap

• New York University D.Malaspina

• Yale University E.Funai• U. of Washington D. Siscovick,

M. Williams• Funding: NIH; NARSAD

• Ministry of Interior• Ministry of Health- Cancer Registry• Ministry of Justice• Central Bureau of Statistics• Hadassah: Legal Bureau and IRB• Hebrew University Cosell Center

AND ALL PARTICIPANTS IN JPS STUDIES